This project will investigate the efficacy of UBS109, a water soluble nuclear factor kappa B (NF-kB ) antagonist structurally related to curcumin, the principal curcuminoid of the Indian curry spice turmeric, to block CNS and behavioral changes in an animal model of cytokine-induced depression. Data suggest that excessive innate immune (inflammatory) responses, including increased signaling through NF-kB pathways, may be an important contributor to major depression (MD). Increased inflammatory immune responses have been found in patients with MD, including increased stress-induced NF-kB DNA binding, which correlates with increased stress-induced proinflammatory cytokine responses. In addition, inflammatory cytokines and their signaling pathways have been shown to interact with multiple pathophysiologic domains relevant to MD including monoamine metabolism, neuroendocrine function, synaptic plasticity and regional brain metabolism. These observations suggest that excessive inflammation and/or increased activity of proinflammatory signaling pathways such as NF-kB may play an important role in the pathophysiology of MD. A significant percentage of MD patients do not respond to conventional antidepressant therapies, and patients who are treatment resistant have been found to exhibit increased inflammatory responses. Thus, a novel treatment approach for MD patients, especially those with treatment resistance, may be to block excessive inflammatory activity through inhibition of NF-kB. Curcumin has shown considerable promise as an anti-inflammatory agent, blocking NF-kB and exhibiting preliminary efficacy in inflammatory and autoimmune disorders. However, curcumin exhibits poor bioavailability due to poor absorption and limited tissue distribution. UBS109 was developed to overcome these limitations, and exhibits greater NF-kB antagonism in combination with improved bioavailability. Given this pharmacodynamic profile, we hypothesize that UBS109 will prevent lipopolysaccharide (LPS)-induced brain inflammatory responses and behavioral changes in mice. To test this hypothesis, we will 1) investigate the effects of UBS109 versus curcumin on LPS-induced peripheral and central NF-kB DNA-binding and NF-kB -dependent gene and protein expression in adult male C57/BL6 mice and 2) study the effects of UBS109 versus curcumin on LPS-induced behavioral changes and their relationship to changes in NF-kB pathway activity. Mice will be treated with LPS (30 ug/mouse) in the presence or absence of acute or chronic UBS109 or curcumin (each at increasing doses), and inflammatory activity (e.g. increased NF-kB DNA-binding and increased cytokine gene &protein expression) in the brain and periphery will be assessed along with both early (e.g. reduced locomotor activity) and later phase (e.g. reduced sucrose preference, decreased struggling in the forced swim test) behaviors. Preliminary experiments will be conducted to establish relevant pharmacokinetics properties to inform chronic UBS109 dosing strategies. Together, these studies will provide "proof of concept" parameters for use of UBS109 in the treatment of MD with increased inflammation. PUBLIC HEALTH RELEVANCE: Recent data indicate that inflammation may contribute to the development of depression and may play a role in depressed patients who fail to respond to conventional antidepressant medications. The proposed studies will explore the effectiveness of the novel anti-inflammatory drug, UBS109, to block behavioral changes in a mouse model of inflammation-induced depression. UBS109 was developed from the natural compound curcumin, an ingredient of the curry spice, turmeric, which exhibits both anti-inflammatory and antidepressant properties.